Biology subjects

Magnitov, M.

Publications and source records attributed to Magnitov, M..

3 recordsLinked to original sources

bioRxiv2021

SETDB1 Fuels the Lung Cancer Phenotype by Modulating Epigenome, 3D Genome Organization and Chromatin Mechanical Properties

Imbalance in the finely orchestrated system of chromatin-modifying enzymes is a hallmark of many pathologies such as cancers, since causing the affection of the epigenome and transcriptional reprogramming. Here, we demonstrate that a loss-of-function mutation (LOF) of the major histone lysine methyltransferase SETDB1 possessing oncogenic activity in lung cancer cells leads to broad changes in the overall architecture and mechanical properties of the nucleus through genome-wide redistribution of heterochromatin, which perturbs chromatin spatial compartmentalization. Together with the enforced activation of the epithelial expression program, cytoskeleton remodeling, reduced proliferation rate and restricted cellular migration, this leads to the reversed oncogenic potential of lung adenocarcinoma cells. These results emphasize an essential role of chromatin architecture in the determination of oncogenic programs and illustrate a relationship between gene expression, epigenome, 3D genome and nuclear mechanics.

cancer biology↗

bioRxiv2021

Rapid depletion of CTCF and cohesin proteins reveals dynamic features of chromosome architecture.

The interphase genome is mainly shaped by cohesin-mediated loop extrusion and cohesin-independent compartmentalization. Extrusion is a dynamic process of cohesin loading, loop extension and release. Cohesin release is mediated by WAPL. Loss of WAPL leads to the formation of longer loops and counters compartmentalization. The dynamics of these changes in chromosome organization have been unclear. We have used acute depletion of WAPL to show that within six hours cohesin accumulates at CTCF-bound loop anchors and extended loops are formed. When we deplete WAPL and CTCF simultaneously, new loops are formed between active genes. Surprisingly, active gene clustering is independent of cohesin. Stabilization of cohesin on chromatin leads to a decrease in compartmentalization, which is rapidly restored by depletion of cohesin. Our analyses show that loop extrusion counters compartmentalization and plays a central role in many aspects of chromosome organization. HIGHLIGHTSO_LICohesin accumulates at CTCF-mediated chromatin loop anchors following WAPL depletion. C_LIO_LIActively transcribed genes form long-range gene clusters independent of the cohesin complex. C_LIO_LIPlumes are a novel architectural feature of juxtaposed DNA formed by cohesin at open chromatin islands. C_LIO_LIChromosome compartmentalization can be uncoupled from nuclear lamina interactions. C_LI

molecular biology↗

bioRxiv2021

FACT-mediated maintenance of chromatin integrity during transcription is essential for viability of mammalian stem cells

Preservation of nucleosomes during replication has been extensively studied, while the maintenance of nucleosomes during transcription has gotten less attention. The histone chaperone FACT is involved in transcription elongation, although whether it disassembles or assembles nucleosomes during this process is still unclear. We deleted the FACT subunit in adult mice to clarify the function of FACT in mammals. FACT loss was lethal due to the loss of the earliest progenitors in bone marrow and intestine, while mor differentiated cells were not affected. Using cells isolated from several tissues, we showed that FACT loss was lethal only for stem cells but not cells differentiated in vitro. FACT depletion led to increased chromatin accessibility in a transcription-dependent manner, suggesting that nucleosomes are lost during transcription in the absence of FACT. The most prominent response to the loss of nucleosomes was the activation of interferon signaling and the accumulation of immunocytes in sensitive organs. FACT maintained chromatin integrity during transcription in mammalian adult stem cells, suggesting that chromatin transcription in these cells is different from more differentiated cells.

systems biology↗